Method for inhibiting adsorption of container-derived contaminants on drugs and contamination-inhibitory containers

ABSTRACT

This invention provides a method for inhibiting adsorption of container-derived contaminants on a powdery or solid drug which comprises establishing a lower alcohol vapor phase within a container made, at least in part, of rubber or a plastic material. The method inhibits adsorption of container-derived substances on a drug to preclude development of insoluble particulate matter owing to said adsorption in an aqueous solution prepared extemporaneously without causing loss of the drug and avoiding the toxic effect of decomposition or degradation of the drug, thus insuring a long-term trouble-free stable shelf-life of the drug.

TECHNICAL FIELD

The present invention relates to a method for inhibiting adsorption ofcontainer-derived contaminants on drugs such as powdery drugs and to acontainer housing a drug in stable condition.

BACKGROUND OF THE INVENTION

Glass containers are mainly used for powdery or solid pharmaceuticalpreparations containing antibiotics, e.g. cefazolin, ampicillin, etc.,or enzymes, e.g. urokinase etc., as active ingredients, while containersmade of almite (aluminum with a surface oxide film), hard glass,stainless steel, or the like are used for accommodating the startingmaterials or synthetic intermediates of drugs and the so-called bulksubstances.

However, containers made of such materials are disadvantageous in thatthe drugs contained are liable to become contaminated with metal orglass fragments upon unsealing.

Recently, containers made of glass (borosilicate glass, soda-lime glass)plus rubber, elastomeric closure or the like came into usage but theywere also found to have the disadvantage that the antioxidant, e.g.2,6-di-t-butyl-4-methylphenol (BHT), vulcanizer, adipic acid derivative,phthalic acid derivative, and other additives, as well as the lubricantoil, e.g. silicone oil, tend to emigrate from the rubber or elastomericclosure and become adsorbed on the drugs to cause insoluble particulatematter.

Research is also being done into the use of plastics for pharmaceuticalcontainers, but polyvinyl chloride (PVC), for instance, has the drawbackthat additives such as dioctyl phthalate (DOP) contained may dissolveout into the interior of the container, while nylon, polyurethane,ethylene-vinyl acetate copolymer (EVA), etc. have the disadvantage thatthe residual unreacted monomer or monomers tend to prevent formation ofa homogeneous solution of the powdery drug. Furthermore, while anadhesive is used in the manufacture of containers from nylon,polyurethane, etc., the solvent used in the adhesive, such as methylethyl ketone, toluene, or xylene, diffuse out and become adsorbed on thedrug as it is the case with said unreacted monomers, thus causingdecomposition, degradation, insoluble particulate matter, and othertroubles inclusive of toxic interactions.

The feasibility of using polyolefins such as polyethylene andpolypropylene is also being assessed by the industry and their usage forpharmaceutical containers is being spreading but these materials alsohave the disadvantage that the process-derived contaminants such asadipic acid or phthalic acid derivatives, oils, low molecularsubstances, the so called wax component, etc. tend to be adsorbed on thedrug powder contained and when the drug powder is dissolved in a solventsuch as water for injection, give rise to insoluble particulate matter.

Thus, each of the known materials for pharmaceutical containers has itsown drawbacks and, therefore, a demand exists for a new method ofovercoming said disadvantages and a new kind of drug container which isfree from the disadvantages.

SUMMARY OF THE INVENTION

The object of the present invention, therefore, is to provide a methodfor providing an improved pharmaceutical container for powdery or othermedicines and a novel improved container.

The inventors of the present invention did much research foraccomplishing the above-mentioned object and discovered that when alower alcohol vapor phase is established as the internal atmosphere of acontainer, the adsorption of potential contaminants derived from thecontainer material, such as rubber or a plastic, on the drug substanceis remarkably inhibited, with the result that the incidence of insolubleparticulate matter (non-homogeneous dissolution) in a solution of thedrug is completely precluded without any appreciable loss of the drugsubstance due to decomposition, degradation, or aging, without entailingany associated toxic reaction, and without detracting from the inherentsolubility of the powdery drug, thus insuring a long-term stability andclinical safety of the drug.

The present invention has been brought into being based on the abovefinding.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view illustrating the presence of a lower alcohol permeablepouch or cell, lower alcohol and drug within the pharmaceuticalcontainer.

DESCRIPTION OF THE SYMBOLS

1 pharmaceutical container

2 lower alcohol-permeable plastic pouch or cell

3 internal atmosphere of the pharmaceutical container

4 matrix impregnated with a lower alcohol or carrying it as adsorbedthereon

5 powdery or solid drug or drug intermediate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of inhibiting adsorption ofcontainer-derived contaminants on a powdery or solid drug characterizedin that, in accommodating a powdery or solid drug preparation, drugmaterial, or drug intermediate (hereinafter referred to sometimes as adrug or equivalent) in a pharmaceutical container 1 made, at least inpart, of rubber, elastomer or a plastic material, a lower alcohol vaporphase is established as the internal atmosphere 3 of the container 1.

More particularly, the present invention provides a method forinhibiting adsorption of container-derived contaminants on a drug orequivalent, wherein a matrix impregnated with a lower alcohol 4 orcarrying it as adsorbed thereon is accommodated in a container 1 so asto establish a lower alcohol vapor phase as the internal atmosphere 3 ofthe container; the same method wherein ethanol is used as said loweralcohol; and the same method as above wherein a lower alcohol-permeableplastic pouch or cell 2 containing a powdery or solid drug or equivalent5 and a matrix impregnated with a lower alcohol or carrying it asadsorbed thereon 4 are accommodated in a container 1 so as to establisha lower alcohol vapor phase as the internal atmosphere of said cell 2.

The present invention further provides a pharmaceutical package form fora powdery or solid drug or equivalent which comprises a container 1made, at least in part, of rubber, elastomer or a plastic material andcontaining a matrix impregnated with a lower alcohol or carrying thesame as adsorbed thereon for establishing a lower alcohol vapor phase asthe internal atmosphere of the container, and a pharmaceutical packageform comprising a lower alcohol-permeable plastic cell 2 containing apowdery or solid drug or equivalent and an outer container containing amatrix impregnated with a lower alcohol or carrying it as adsorbedthereon for establishing a lower alcohol vapor phase as the internalatmosphere of said cell 2.

The drug that can be used in the present invention includeswater-soluble powdery or solid drugs which can be directly administeredto man and other animals, including but not limited to antibiotics suchas cephazolin and other cephem antibiotics, ampicillin and otherpenicillin compounds, imipenem and other carbapenem antibiotics,vancomycin and other polypeptide antibiotics, erythromycin and othermacrolide antibiotics, etc., bioactive substances (native andrecombinant bioactive substances) such as interferons (INF),interleukins (IL), vaccines, erythropoietins (EPO), granulocyte colonystimulating factor (GCF), immunoglobulins, urokinase and other enzymes,vitamins, platelet activating factor (PAF), water-soluble steroids(adrenocorticoids) and other hormones, and synthetic inhibitors ofenzymes which are not naturally occurring, among others. Thepharmaceutical intermediates include synthetic intermediates andproduction intermediates of the above-mentioned and other drugs.

When any of these drugs is accommodated in a container made of rubber,elastomer and/or plastic material, it undergoes interaction with varioussubstances originating from the container material or materials toadsorb them.

Typical of said container-derived substances or contaminants are variousadditives, e.g. antioxidants such as BHT, DOP, vulcanizers, adipic acidderivatives, phthalic acid derivatives, etc., oils such as silicone oil,unreacted monomers, and organic volatile solvents for adhesives, such asmethyl ethyl ketone, toluene, xylene, etc.

The lower alcohol that can be used for establishing said lower alcoholvapor phase as the internal atmosphere of the container includesethanol, a representative alcohol, methanol, propanol, isopropylalcohol, etc. Among them, ethanol is particularly preferred when thedrug is to be directly administered. However, when a syntheticintermediate or the like of the active ingredient, such as a productionbulk powder, the lower alcohol need not be ethanol but other loweralcohols may be employed with equal success.

The preferred technology for establishing a lower alcohol vapor phase asthe internal atmosphere of the container in accordance with the presentinvention includes the method in which a matrix impregnated with a loweralcohol or carrying it as adsorbed thereon is accommodated alongside adrug in the container 1 and the double-packaging method in which a loweralcohol-permeable cell 2 filled with a powdery or solid drug isaccommodated alongside a matrix impregnated with a lower alcohol orcarrying it as adsorbed thereon in said container 1.

There is no particular limitation on the kind of matrix to beimpregnated with a lower alcohol or on which a lower alcohol is to beadsorbed. Typically, however, inorganic porous substances such as silicagel, diatomaceous earth, celite, zeolite, activated carbon, alumina,etc., cellulose and its derivatives, dextrins, polysaccharides,synthetic polymers such as polypropylene, polyurethane, etc., and otherhigh-porosity formed substances can be mentioned. It is also possible toemploy nonwoven fabrics manufactured from said polymers or formedsubstances.

Impregnation of the matrix with a lower alcohol or adsorption of a loweralcohol on the matrix can be carried out in the per se known manner.There also is no particular limitation on the ratio of the lower alcoholto the matrix. The saturation point is generally used as a reference butthe lower alcohol may be used in a sub-saturation amount. When, forexample, the matrix is zeolite which has a high hygroscopic capacity,the preferred proportion of the lower alcohol may be not less than 51%saturation. There is no particular limitation on the amount of thematrix impregnated with the lower alcohol or carrying it as adsorbedthereon to be contained in the container. Thus, the amount can beliberally selected only if the lower alcohol vapor phase effective foraccomplishing the object of the invention may be established within thecontainer. Taking a container having a capacity of 20-100 cubiccentimeters and containing a powdery drug as an example, it is possibleto obtain a lower alcohol vapor phase sufficient to accomplish theobject of the invention by dripping 1 μl of distilled ethanol on theinside wall of the container.

In the method of the present invention wherein a matrix impregnated witha lower alcohol or carrying it as adsorbed thereon is accommodated forestablishing a lower alcohol vapor phase as the internal atmosphere ofthe container and said matrix is one having a large hygroscopic capacitysuch as zeolite or alumina, it is preferable to further accommodate amoisture-releasing disoxidation agent in the container. The reason isthat when the interior of the container is very dry, the lower alcoholin said matrix is hard to be released into the internal atmosphere butwhen said moisture-releasing disoxidation agent is concomitantlypresent, the moisture released therefrom is adsorbed on said matrix insubstitution for said lower alcohol, with the result that the loweralcohol is released effectively from the matrix into the internalatmosphere of the container.

There is no particular limitation on the shape and size of the containerfor use in the present invention only if it is made, at least in part,of rubber, elastomer or a plastic material and the kind of rubber,elastomer or plastic material may also be any of the kinds known to beuseful for pharmaceutical containers. For example, the rubber that canbe used includes natural rubber, butyl rubber, isoprene rubber, etc.,while the plastic material includes but is not limited to polyolefinssuch as polyethylene, polypropylene, etc., polyvinyl chloride,polyamide, polyurethane, ethylene-vinyl acetate copolymer, polyethyleneterephthalate, polyvinylidene chloride, and polyvinyl alcohol.

The pharmaceutical container made, at least in part, of rubber,elastomer or plastic material as mentioned throughout this specificationincludes glass containers including rubber or elastomeric closure,plastic film containers, and laminate containers consisting of an innerlayer comprising a plastic film and an outer layer comprising analuminum foil, among other containers.

In addition to the above method of inhibiting adsorption ofcontainer-derived substances on the drug powder or the like, the presentinvention provides a drug container suited for implementation of theabove method. This drug container is made, at least in part, of rubber,elastomer or plastic material and contains a matrix impregnated with alower alcohol or carrying it as adsorbed thereon for establishing alower alcohol vapor phase therein so that, when a powdery or solid drugis filled therein, adsorption of container-derived substances on thedrug may be positively inhibited and the drug can thereby be kept instabilized condition for a long period of time.

The material that can be used for the fabrication of said pharmaceuticalcontainer 1 according to the present invention is preferably highlyimpermeable to lower alcohol vapors and moisture. As examples of suchmaterial, there can be mentioned a polyolefin film-aluminum foillaminate, a resin film made of, for example, polyethylene terephthalate,polyvinylidene chloride, polyvinyl alcohol, polyamide, or saponifiedethylene-vinyl acetate copolymer, and a laminate film comprising suchresin films.

According to one embodiment of the pharmaceutical container according tothe present invention, the drug is accommodated in a loweralcohol-permeable plastic cell 2 and, as such, is further accommodatedalongside said matrix in a container 1 (double-packaged form).

In this form of container, the drug is protected from direct contactwith an outer packaging material, i.e. said container 1, so that theabove-mentioned disadvantages caused by adsorption of container-derivedsubstances on the drug are avoided. However, a similar problem maydevelop owing to adsorption of substances derived from plastic cell 2,which is the inner packaging material. However, this problem is neatlysolved by utilizing said matrix impregnated with a lower alcohol orcarrying it as adsorbed thereon in accordance with the presentinvention.

Thus, when said matrix is accommodated alongside said drug-containingcell 2 in the container 1, the vapor of the alcohol from the matrixpermeates through the wall of cell 2 and diffuses into the cell 2 toestablish a lower alcohol vapor phase within the cell 2 to accomplishthe object of the invention.

Therefore, the cell 2 must be made of a material permeable to the loweralcohol. As examples of such material, there can be mentionedpolyolefins, e.g. polyethylene and polyvinyl chloride. There are casesin which the above permeability to a lower alcohol can be insured notonly by selecting the proper material for the cell 2 but also by varying(reducing) the thickness of the cell. Therefore, the term "loweralcohol-permeable" as used referring to cell 2 is not an absolute termbut a relative term in relation to the permeability of the container 1.

BEST MODE OF PRACTICING THE INVENTION

To describe the present invention in further detail, some examples ofproduction of the matrix for use in the method of the invention aregiven as reference examples and, then, examples of working the method ofthe invention and test examples for demonstrating the effect of workingthe method are described.

REFERENCE EXAMPLE 1

A zeolite matrix with a pore size of not less than 3 angstrom units(pore diameters are not uniform but have a normal distribution) wasimmersed in distilled ethanol and allowed to stand there at roomtemperature for 24 hours. The matrix was then withdrawn from the ethanolbath and the excess ethanol, mostly adherent on the surface of thematrix, was removed by means of zeolite-passed nitrogen gas, dry air, orhot nitrogen gas, or hot dry air. In this manner, an ethanol-saturatedzeolite matrix was obtained.

This ethanol-saturated zeolite was optionally mixed with a predeterminedproportion, e.g. half the weight of the ethanol-saturated zeolite, ofthe untreated zeolite to provide an ethanol-impregnated matrix for usein the invention.

REFERENCE EXAMPLE 2

A carrier made of zeolite with a pore diameter of not less than 3angstrom units was put in a glass desiccator containing distilledethanol in its bottom and allowed to stand at room temperature for 2weeks to provide an ethanol-saturated zeolite matrix.

Optionally. this ethanol-saturated zeolite was mixed with apredetermined proportion of the untreated zeolite to provide anethanol-impregnated matrix for use in the invention.

REFERENCE EXAMPLE 3

A glass column was packed with alumina with a pore diameter of not lessthan 3 angstrom units. Then, hot dry air was passed through distilledethanol (recycling) to generate ethanol gas and the ethanol gas waspassed through the column for 24 hours to provide an ethanol-saturatedalumina matrix.

This ethanol-saturated alumina was optionally mixed with a predeterminedproportion of the untreated alumina to provide an ethanol-impregnatedmatrix for use in the invention.

REFERENCE EXAMPLE 4

Using nonwoven fabrics made of cellulose (inclusive of cotton) andpolypropylene, respectively, in lieu of zeolite, the procedure ofReference Example 1 was otherwise repeated to provideethanol-impregnated matrices.

REFERENCE EXAMPLE 5

Using a porous artifact (e.g. sponge) made of polyurethane resin in lieuof zeolite, the procedure of Reference Example 1 was otherwise repeatedto provide an ethanol-impregnated matrix.

EXAMPLE 1

Zeolite (Tosoh Corporation, Zeolite ZA4, 9-14 mesh) was saturated withethanol by the procedure of Reference Example 1 to provide matrix A.

As a highly hygroscopic drug substance, 2 grams (potency) of thecommercial lyophilized antibiotic cefmetazole sodium (trade name:Cefmetazon, Sankyo; hereinafter referred to briefly as CMZ) wassubjected to the following test.

While the commercial CMZ 2 g (potency) is a product available in a glassvial the CMZ cake was comminuted with a stainless steel microspatula andthe resulting powder was filled in a bag (10 cm×10 cm) made of 200μm-thick low-density polyethylene (LDPE, Showa Denko, MFR, 3.0 g/10 min,d=0.926-0.927) film. (The above operation was performed in anenvironment with a relative humidity of not more than 25%).

Product A of the invention was prepared by accommodating theabove-mentioned CMZ-containing LDPE bag, said matrix A, and adisoxidation agent (Ageless Z10P, Mitsubishi Gas Chemical; hereinafterreferred to briefly as Z10P) in a 14 cm×14 cm bag made ofaluminum-laminated plastic film and sealing the bag. Meanwhile, analuminum foil strip was coated with 100 ppm each of diethylhexylphthalate (DEHP) and di-n-butyl phthalate (DNBP), both of which aresubstances interfering with the solubility of the drug, and the coatedfoil strip was put in the above aluminum-laminated plastic film bag.

As a control, the same CMZ-containing LDPE bag and samecontaminants-coated foil strip as above were accommodated in a 14 cm×14cm bag of aluminum-laminated plastic film and the bag was thenheat-sealed.

The commercial vial was pierced using a gas syringe-needle forreplacement of the internal atmosphere with nitrogen gas and subjectedto the same test as vial control.

Each of the above test samples was maintained at 60° C., 75% R.H. (aconstant temperature-constant humidity chamber PR-4ST, Tabai-Espec) for1 and 2 weeks and the oxygen concentration in the bag was determined. Atthe same time, both appearance and potency (by HPLC) were tested by themethods prescribed in the Minimum Requirements for Antibiotic Productsof Japan 1992. The oxygen concentration was measured with TorayEngineering's zirconia oxygen meter LC800. For potency assays, ShimadzuHigh Performance Liquid Chromatograph LC-9A was used.

In addition, 2 g (potency) of CMZ was dissolved in 20 ml of purifiedwater and the turbidity of the solution was measured with HACH'snephelometer 43900.

The test results are presented in Table 1.

                  TABLE 1    ______________________________________             Storage Product A          Glass    Test     period  of the     Control vial    sample   (weeks) invention  product product    ______________________________________    Appearance             0       White      White   White             1       White      White   White             2       White      White   White    Oxygen   0       20.6       20.4    N.D..sup.*    concentration             1       0.73       20.6    N.D..sup.*    (%)      2       0.00       20.4    N.D..sup.*    Potency  0       948        948     945    (μg/mg)             1       940        944     946             2       933        928     929    Alcohol  0       Intense odor                                Not tested                                        Not tested    odor     1       Intense odor                                Not tested                                        Not tested             2       Intense odor                                Not tested                                        Not tested    Turbidity.sup.#             0       0.24       0.24    0.21             1       0.31       1.81    0.22             2       0.26       2.87    0.44    ______________________________________     N.D..sup.* = not determinable because the glass vial has been hermeticall     closed under nitrogen gas.     Turbidity.sup.#  = mean of n = 3.

It should be noted that neither DEHP nor DNBP was added to the glassvial control.

It is clear from the above table that, according to product A of theinvention, the highly hygroscopic drug CMZ can be maintained withoutdegradation and that the release of alcohol from product A is efficientenough to inhibit development of turbidity.

EXAMPLE 2

Zeolite (Zeolite ZA4, 9-14 mesh) was impregnated with ethanol by theprocedure described in Reference Example 3 to provide 75%saturatedmatrix B.

On the other hand, one gram (potency) of lyophilized antibioticcefazolin sodium (hereinafter referred to as CEZ), a highly hygroscopicdrug substance, was filled in a cell (10 cm ×10 cm) made of linearlow-density polyethylene film (LLDPE, d=0.920, Mitsui Petrochemical, 175μm). This cell, the above matrix B, and the disoxidation agent Z10P (onepiece) were put in a 12 cm×12 cm bag made of polyvinylidene chloride(PVdc) barrier film (Fujimori Kogyo, inside dimensions 10 cm×10 cm) andthe bag was heat-sealed to provide product B of the invention.

The above bag was maintained at 60° C., 75% R.H. (a constanttemperature-constant humidity chamber AG328, Advantech Toyo) for 1 and 2weeks. The gas in the bag was sampled by means of a gas trapping syringeand its alcohol concentration was measured using Shimadzu GasChromatograph GC8A, while the oxygen concentration was measured withToray Engineering's zirconia oxygen meter LC800. In addition, thepotency of CEZ was assayed by HPLC (Shimadzu High Performance LiquidChromatograph LC-9A) and the moisture content was determined withMitsubishi Kasei's water microassay apparatus CA-06. The potency andmoisture content determinations were in accordance with the MinimumRequirements for Antibiotic Products of Japan 1992.

The test results are presented in Table 2.

                  TABLE 2    ______________________________________                  Storage period                             Product B of    Test sample   (weeks)    the invention    ______________________________________    Appearance    0          White                  1          White                  2          White    Oxygen        0          20.4    concentration 1          0.0    (%)           2          0.0    potency       0          940    (μg/mg)    1          933                  2          927    Moisture      0          0.45    content       1          0.53    (%)           2          0.48    Alcohol       0          0.5    concentration 1          7.8    (%)           2          18.1    ______________________________________

It is apparent from the above table that with product B of theinvention, the highly hygroscopic drug substance CEZ can be maintainedwithout degradation and that matrix B releases a sufficient amount ofalcohol.

EXAMPLE 3

A mixture of active alumina and celite was molded into a board (about4×3 cm, about 5 g) and this board was impregnated with 15% by weight ofmethanol (Wako Pure Chemical Industries, reagent special grade) bydripping to provide matrix C. This matrix was covered with a nonwovenpolypropylene cloth.

Then, as an antibiotic bulk, 5 grams of cefazolin sodium (CEZ) bulkpowder with a moisture content of 2% (bulk potency =870 μg/mg) was putin a glass bottle of 250 ml capacity. The bottle was closed with a rednatural rubber stopper coated with 100 ppm of DEHP and 100 mg ofparaffin on the inner surface and the top was masked with a PVC tape topreclude infiltration of moisture. This product was used as a control.

On the other hand, product C of the invention was prepared using samematerials as above and by making an incision in a similarly coatedrubber stopper and inserting matrix C in the incision at an obliqueangle.

The above two products were maintained at 60° C., 75% R.H. (a constanttemperature-constant humidity chamber AG328, Adventech Toyo) for 1 and 2weeks and the potency of the antibiotic, appearance, and turbiditynephelometer reading) were determined as in the preceding examples. Theresults are presented in Table 3.

                  TABLE 3    ______________________________________              Storage     Products C    Test      period      of the    Control    sample    (weeks)     invention product    ______________________________________    Appearance              0           White     White              1           White     White              2           White     White    Potency   0           100 before                                    100 before    (μg/mg)              1           97.8      96.4              2           90.2      91.3    Alcohol   0           Intense odor                                    Not tested    odor      1           Intense odor                                    Not tested              2           Intense odor                                    Not tested    Turbidity.sup.#              0           2.78      2.78              1           2.99      8.56              2           2.83      17.54    ______________________________________     Turbidity.sup.#  : same as Table 1.

It is clear from the above table that with product C of the invention,the bulk drug is protected against the trouble of insoluble particulatematter, thus indicating the effectiveness of product C in the qualitymaintenance of the drug. Thus, since rubber closure-derived contaminantstransferred to a bulk drug would pass through a 0.2 μm filter, it isimportant to preclude chances for transfer of the contaminants from thebulk stage. This trouble can be successfully avoided by the use of theproduct of the invention. Moreover, any residue of the alcohol used inthe product of the invention can be easily eliminated by, for example,freeze-drying so that the risk of contamination of the drug can besuccessfully prevented.

INDUSTRIAL APPLICABILITY

In accordance with the present invention, as the result of establishingthe vapor phase of a lower alcohol within a container housing a powderyor solid drug or equivalent which is liable to undergo interaction withcontainer-derived substances, adsorption of contaminants on the drug isprecluded and the solubility of the drug is fully maintained to preventdevelopment of insoluble particulate matter in a solution preparedextemporaneously. Moreover, the degradation of the active drug substanceowing to said adsorption is completely prevented, thus permittingpackaging of the drug in a plastic or other container without the riskof toxic interactions.

What is claimed is:
 1. A method of inhibiting adsorption ofcontainer-derived contaminants on a water-soluble powdery or solid drugor drug intermediate in a container made, at least in part, of rubber,elastomer or plastic material which comprises establishing a loweralcohol vapor phase within said container which includes said powdery orsolid drug or drug intermediate.
 2. The method according to claim 1wherein said lower alcohol vapor phase is established by accommodating amatrix impregnated with the lower alcohol or carrying it as adsorbedthereon in said container.
 3. The method according to claim 1 or 2wherein said lower alcohol is ethanol.
 4. A method of inhibitingadsorption of container-derived contaminants on a water-soluble powderyor solid drug or drug intermediate which comprises filling said powderyor solid drug or drug intermediate in a lower alcohol-permeable plasticcell, accommodating the cell in a container made, at least in part, ofrubber, elastomer or a plastic material, and establishing a loweralcohol vapor phase within said container which includes said powdery orsolid drug or drug intermediate.
 5. A package for inhibiting adsorptionof container-derived contaminants on a water-soluble powdery or soliddrug or drug intermediate which comprises an outer container comprisingrubber, elastomer or a plastic material, wherein (a) said powdery orsolid drug or drug intermediate and (b) a matrix impregnated with alower alcohol or carrying it as adsorbed thereon for establishing alower alcohol vapor phase as the interal atmosphere of said outercontainer, are present within said container.
 6. The package accordingto claim 5, further comprising a lower alcohol-permeable cell withinsaid container, wherein said cell contains said powdery or solid drug ordrug intermediate,and wherein said matrix impregnated with a loweralcohol or carrying it as adsorbed thereon for establishing a loweralcohol vapor phase, is also present within said container.
 7. A methodof inhibiting adsorption of container-derived contaminants on awater-soluble powdery or solid drug or drug intermediate which comprisesfilling said powdery or solid drug or drug intermediate in a loweralcohol-permeable plastic cell, accommodating the cell in an outercontainer made, at least in part, or rubber, elastomer or a plasticmaterial, and additionally accommodating within said outer container amatrix impregnated with a lower alcohol or carrying it as adsorbedthereon for establishing a lower alcohol vapor phase as the internalatmosphere of the container.